Intrauterine Growth Retardation Induced Long-Term Gene Dysregulation Is Associated with Altered Histone Modifications in Rat Islets

Abstract

Intrauterine growth retardation (IUGR) is associated with the development of type 2 diabetes in adulthood. Although the underlying mechanisms remain unclear, permanent alterations in gene expression implicate epigenetics. Using a rat model of IUGR induced by bilateral uterine artery ligation at e18, we sought to determine if histone modifications are a potential mechanism for permanent IUGR-induced gene dysregulation. We assessed genome-wide histone modifications in islets from 2 and 10 week control and IUGR rats using ChIP-Seq. IUGR induced significant changes in enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in 2 week islets at 2181, 1482, and 4572 annotated genes, respectively. At 10 week there were far more changes in enrichment of these marks (9988, 3489, and 4355 genes, respectively). We then integrated our RNA-Seq transcriptome data obtained at the same ages and found that the expression levels of multiple genes in IUGR islets were correlated with changes in histone marks. In 10 week islets, the expression of 639, 355, and 400 genes correlated with changes in enrichment of H3K4me3, H3K27me3, and H3K27Ac, respectively; whereas in 2 week islets, only 43, 64, and 149 genes were correlated with enrichment of these marks. Interestingly, 6 genes in 10 week islets correlated with changes in all 3 histone marks, strongly suggesting that changes in gene expression were induced by histone modifications. Ingenuity pathway analysis of differential expressed genes that correlated with histone modifications revealed significant enrichment in pathways critical for normal islet function, such as cAMP-mediated signaling, immune function, axonal guidance, and VEGF family ligand-receptor interaction. Collectively, the present findings identify histone modification as a potential epigenetic mechanism that may contribute to long-term gene dysregulation and abnormal islet phenotype in IUGR animals. Disclosure Y. Lien: None. P. Wang: None. R.A. Simmons: None.